1-benzamido-1-phenyl-3-piperidinopropane and salts thereof



United States Patent "ice 235mm Patented Sept. 2, 1958 The bases of the new compounds are solids at room tem- 2,850,498 perature. They are relatively insoluble in water, but

are soluble in the common polar organic solvents. The acid addition salts of those bases are in general Watersoluble, crystalline substances.

l-BENZAMIDO-l-PHENYL-3-PIPERIDINOPROPANE AND SALTS THEREOF Albert Pohland, Indianapolis, 11111., assignor to Eli Lilly The new substituted benzamidopiperidinopropanes and and Company, Indianapolis, Ind., a corporation of their salts are local anesthetics characterized by stability, Indiana lack of irritation and long duration of action. For

Y therapeutic use, the compounds can be advantageously No gg i is fi ggfg 1953 10 utilized as water solutions of the acid addition salts, or the salts or bases can be incorporated into various 3 Claimspharmaceutical extending media such as ointments, solutions, jellies, oils, lotions, suspending media and the like. This invention relates to substituted benzamidopropyl- The new compounds can be prepared by methods known amines and more particularly to substituted 1-benzamidoto the art, exemplified by the following series of 3-piperidinopropanes and their acid addition salts, and to equations, in which R and R have the same significance the preparation thereof. as hereinabove.

CH2-CH2 CH2CHz HONHZ O=COH-CHz-N 0H2 HON=C-- OH-CH -N CH;

I l! CHz-Cz R1 CHr-Cfia R1 CHz-CH? The bases of the substituted benzamidopiperidinopro- Referring to the equations, it will be seen that a subpanes of the present invention may be represented by the stituted piperidinopropiophenone is treated with hydroxformula ylamine to produce the corresponding oxime, which is hydrogenated to form a substituted phenylpiperidinopropylamine. The piperidinopropylamine is reacted with a substituted benzoyl chloride to form the correspondingly substituted benzamidopiperidinopropane.

CHFCH, As will be evident, the compounds contain a basic I nitrogen atom, which can react with acids to form acid RTQ'CONHOHLQHOHN addition salts. Such salts are readily prepared by the R1 UHF-CH2 usual methods of the art, e. g., the reaction of stoichiometrically equivalent amounts of the desired base and a selected acid in a mutual inert solvent. Examples wherein R represents amember of the group consisting of of acids which are suitable for the preparation of acid hydrogen and a cyclohexyloxy radical and R represents addition salts of the invention are inorganic acids, for a member of the group consisting of hydrogen and :1 example, hydrochloric, nitric, sulfuric, phosphoric, and methyl radical. the like acids; and organic acids, for example, benzoic,

'for one hour at 70 to 110 C.

This application is a continuation-in-part of'my copending application Serial Number 319,783, filed November 10, 1952, now abandoned.

The following examples more specifically illustrate the preparation and properties of the compounds of this invention.

EXAMPLE 1 Preparation of I-benzamid-]-phe/zyl-3-piperinopropane hydrochloride A mixture of 101.5 g. of B-piperidinopropiophenone hydrochloride, prepared'by the method of Adams, Organic Reactions 1, 329 (1942), 31.4 g. of hydroxylamine hydrochloride, 33.6 g. of sodium bicarbonate and 200 ml. of water was allowed to stand at room temperature overnight. A solution of 43 g. of sodium hydroxide in 43 ml. of waterwas added to the reaction mixture and after cooling, the precipitated fl-piperidinopropiophenone oxime was removed by filtration. Afterrecrystallization from methanol, the B-piperidinopropiophenone oxime thus prepared melted at 152-153 C.

Analysis.Calculated for Found: N, 11.75.

fl-Piperidinopropiophenone oxime hydrochloride melted at about 190-191 C. after recrystallization from methanol-ethyl acetate mixture.

Analysis.Calculated for C H N OCI: N,.10.40; Cl, 13.19. Found: N, 10.00; Cl, 1 3.13.

CmHgoNzOi N, 12.07.

crystalline precipitate of 1-benzamido-1-phenyI-3-piperi- 'dinopropane after recrystallization from a mixture "of'ethyl' acetate and petroleum ether melted at about 111112 C.

Analysis.-Calculated for C H N O: N, 8.09.'Found: N, 8.25.

EXAMPLE 3 Preparation of l-benzamido-2-methyl-lphenyl-3-piperidinopropane hydrochloride a-Methyl-B-piperidinopropiophenone prepared I according to the method'of- Ruddy, J.-A. C. S. 72, 718,(1950 was condensed with hydroxylamine to form a-meth'yl-B- piperidinop'ropiophenone oxime. The oxime was reduced with Raney nickel according to the procedure of Example 1 to form 1-phenyl-2-methyl-3-piperidinopropylamine.

1-phenyl-2-methyl-3-piperidinopropylamine thus prepared boiled at about l2 8l29 C. at a pressure 0150.5 mm. of mercury. The index ef-refraction at-'C.'was

A mixture of 9.7 g. of -1-phenyl-2-methyl-3-piperidinopropylamine, 9.7 ml. of benzoyl chloride, 20 ml. of dry pyridine and 100ml. of benzene was allowed to stand for about sixteen hours at room temperature. A suflicient 5 amount of ethyl ether was added to the reaction mixture A mixture of 10 g. of Raney nickel catalyst, 81.5 g.-

of B-piperidinopropiophenone oxime, 200 ml. of ethanol and 75 ml. of liquid ammonia was placed in an autoclave, and reduced under 1400 lbs. pressure of hydrogen melted at about 150-15? 0.

Analysis.-Calculatedfor CgzHaoNzOgI C, 58.65; H, 6.71; N, 6.22. Found: C, 58.88; H, 6.73; N, 6.48.

A mixture of 24 g. of 1-phenyl-3-piperidinopropyl amine, 24 ml. of benzoyl chloride, 300 ml. of benzene and ml. of dry pyridine was allowed to stand at room temperature for about sixteen hours. A sufficient amount of ethyl ether was thereafter added to bring about complete precipitation of the l-benzamido-l-phenyl-3-piperidinopropane hydrochloride formed in the reaction. The precipitate was removed by filtration and recrystallized from a mixture of isopropanol and ether.

1-benzamido-1-phenyl-3-piperidinopropane hydrochloride thus prepared melted at about 188l89 C.

Analysis.Calculated for C H N oCl; N, 7.81; Cl, 9.88.' Found: N, 7.90; Cl, 9.92.

EXAMPLE 2 Preparation 0] 1-benzamid0-J-phenyl-3-piperidinopropane in about 100 ml. of hotethyl'acetate and petroleum,

ether was added until crystallization occurred. The

The reaction mixture to bring about a complete precipitation of the l-ben zamido1-phenyl-2 -metl1yl-3-piperidinopropane hydrochloride formed in the reaction. The precipitate was separated, and after recrystallization from a mixture of ethyl acetate and methanol, the l-benzarnido-1-phenyl-2-methyl-3 piperidinopropane hydrochloride melted at about 262- 263 C., with decomposition.

Analysis.-Calculated for C H H OCI: N, 7.51; Cl, 9.51. Found: N, 7.46; CI, 9.40.

l-ben'z'amido-1-phenyl-2-methyl 3 piperidinopropane. was prepared from 1-benzamido-l-phenyl-2-methyl-3- piperidinopropane hydrochloride by the procedure of Example 2.

- EXAMPLE'4 Preparation of I (4 -cyclohexyloxybenzamido) 1-phenyl 3 piperidin0pr0pane hydrochloride 1-phenyl-3-piperidinopropylamine was prepared according to the process of Example 1. A mixture of 5.8 g. of 4-cyclohexyloxybenzoyl chloride, 8 ml. of pyridine, 4 g. of 1-phenyl-3-piperidinopropylamine and 50 ml. of henzene was warmed on a steam bath for about one hour. The reaction mixture was cooled, and sufiicient ether was added to bring about complete precipitation of the 1-(4'- cyclohexyloxybenzamido)-l-phenyl 3 piperidinopropane By subjecting '1-(4-cyclohexyloxybenzamido}l-phenyl- 3-piperidinopropane hydrochloride to the procedure of .Example 2, there was obtained l-(4'-cyclohexyloxybenzamido)-1-phenyl-3-piperidinopropane.

EXAMPLE 5 Preparation of 1-(4-cycl0hexyl0xybenzamid0) -1-phenyl- 2 methyl-.i-piperidinopropane hydrochloride A reaction mixture containing 10 g. of 1-phenyl-2- methyl-3-piperidinopropylamine prepared according to the procedure of Example 3, 13.8 g. of p-cyclohexyloxybenzoyl chloride, 20 ml. of drypyridine and ml. of,

' benzene was refluxed on a steam bath for aboutone hour.

The reaction mixture was diluted with about. ml. of

ethyl acetate, and cooled, whereupon 1-(4-cyclohexyloxy-.;

benzamido)-1-phenyl-2-methyl 3 piperidinopropane hy- Analysir-Calzifilatedfor C 'H 'N N, 12.06. Found:

drochloride precipitated. The precipitate was removed by filtration and was crystallized from ethyl acetate, whereupon 1-(4-cyclohexyloxybenzamido) 1 phenyl-2- methyl-3-piperidinopropane hydrochloride was obtained, melting at about 220221 C. with decomposition.

Analysis.Calculated for C H N o -Hclz Cl, 7.53. Found: Cl, 7.31.

1-(4-cyclohexyloxybenzarnido) 1 phenyl-2-methyl-3- piperidinopropane base was prepared from 1-(4'-cyclohexyloxybenzamido) l phenyl 2 methyl-B-piperidinopropane hydrochloride by the procedure of Example 2.

EXAMPLE 6 Preparation 0) I -benzamid0-1 -phenyl-3-piperidin0pr0- pane maleate To a solution of 32.2 g. of l-benzamido-l-phenyl-B- piperidinopropane (prepared according to the procedure of Example 2) in 100 ml. of ethanol is added a solution of 3.8 g. of maleic acid in 10 ml. of ethanol. The solution is thoroughly mixed, and evaporated to dryness in vacuo, whereby the maleic acid salt of l-benzamido-lphenyl-3-piperidinopropane is recovered.

By following the above-described procedure, except that sulfuric acid, citric acid, phosphoric acid, lauric acid, acetic acid and butyric acid are used, the sulfate, citrate,

phosphate, laurate, acetate and butyrate salts of l-benz- CHI-CH1 2. l-benzamido-l-phenyl 3 piperidinopropane hydrochloride.

3. A compound of the group consisting of l-benzamido- 1-phenyl-3-piperidinopropane and acid addition salts thereof.

References Cited in the file of this patent UNITED STATES PATENTS Pohland May 31, 1957 OTHER REFERENCES Cromwell et a1.: J. Am. Chem. Soc. 64: 24325 (1942). Cromwell et al. J. Am. Chem. Soc. 66: 870-1 (1944). 

3. A COMPOUND OF THE GROUP CONSISTING OF 1-BENZAMIDO-1-PHENYL-3-PIPERIDINOPROPANE AND ACID ADDITION SALTS THEREOF. 